Marijuana is the most commonly used illicit drug in the United States. Although its use and potential health consequences are widespread and basic science research on cannabinoids is well developed, little research has focused on the clinical treatment of marijuana use disorders. Preclinical and clinical studies implicate cannabinoid interactions with the serotonin system. Vilazodone, a compound combining serotonin reuptake inhibition and 5-HT1A partial agonism, has recently become available. Given its dual serotonergic mechanism of action, vilazodone may have promise as a treatment for marijuana dependence. Therefore, we propose to conduct a randomized, placebo-controlled trial of vilazodone in marijuana-dependent adults. A contingency management intervention coupled with motivational enhancement therapy will be incorporated to encourage study engagement and retention. Further, genomic DNA will be extracted to characterize subjects according to polymorphisms of genes relevant to the 5-HT1A receptor activity, specifically the C-(1019) G variant. We hypothesize that individuals who receive vilazodone treatment combined with MET and CM will have improved marijuana use outcomes compared to individuals receiving a placebo treatment combined with MET and CM. Further, as genetic variations in 5-HT1A receptors have been identified, and may alter the response to vilazodone, we propose to extract genomic DNA to characterize subjects according to polymorphisms of genes relevant to 5-HT1A receptor activity. We hypothesize that individuals with functionally deficient 5-HT1A receptors will have poorer treatment outcomes than individuals without functional deficiency at the 5-HT1A receptor. Results from this study could lead to the development of a new pharmacotherapy for marijuana dependence and increase our knowledge of a potential genetic biomarker for prediction of outcomes. . PUBLIC HEALTH RELEVANCE: Marijuana is the most commonly used illicit drug, yet few clinical trials have evaluated pharmacotherapy treatments for marijuana dependence. This study will evaluate the efficacy of vilazodone for reducing marijuana use in marijuana-dependent adults. A contingency management intervention and motivational enhancement therapy will be incorporated to encourage study engagement and retention, and genomic DNA will be extracted to characterize subjects according to polymorphisms of genes potentially relevant to the activity of vilazodone.